title: Integrative annotation of variants from 1092 humans: application to cancer genomics.
abstract: Interpreting variants, especially noncoding ones, in the increasing number of personal genomes is challenging. We used patterns of polymorphisms in functionally annotated regions in 1092 humans to identify deleterious variants; then we experimentally validated candidates. We analyzed both coding and noncoding regions, with the former corroborating the latter. We found regions particularly sensitive to mutations ("ultrasensitive") and variants that are disruptive because of mechanistic effects on transcription-factor binding (that is, "motif-breakers"). We also found variants in regions with higher network centrality tend to be deleterious. Insertions and deletions followed a similar pattern to single-nucleotide variants, with some notable exceptions (e.g., certain deletions and enhancers). On the basis of these patterns, we developed a computational tool (FunSeq), whose application to ~90 cancer genomes reveals nearly a hundred candidate noncoding drivers.
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Ekta
authors.initials: E
authors.lastname: Khurana
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.|Institute of Genetics and Biophysics, National Research Council (CNR), 80131 Naples, Italy.
authors.forename: Vincenza
authors.initials: V
authors.lastname: Colonna
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
authors.forename: Xinmeng Jasmine
authors.initials: XJ
authors.lastname: Mu
authors.affiliation: Center for Statistical Genetics, Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Hyun Min
authors.initials: HM
authors.lastname: Kang
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.|Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland.|Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.
authors.forename: Tuuli
authors.initials: T
authors.lastname: Lappalainen
authors.affiliation: Institute for Precision Medicine and the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USA.|The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sboner
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
authors.forename: Lucas
authors.initials: L
authors.lastname: Lochovsky
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.|Integrated Graduate Program in Physical and Engineering Biology, Yale University, New Haven, CT 06520, USA.
authors.forename: Jieming
authors.initials: J
authors.lastname: Chen
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Arif
authors.initials: A
authors.lastname: Harmanci
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA.|Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Jishnu
authors.initials: J
authors.lastname: Das
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Alexej
authors.initials: A
authors.lastname: Abyzov
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Suganthi
authors.initials: S
authors.lastname: Balasubramanian
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Beal
authors.affiliation: Institute for Precision Medicine and the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USA.
authors.forename: Dimple
authors.initials: D
authors.lastname: Chakravarty
authors.affiliation: Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Challis
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Declan
authors.initials: D
authors.lastname: Clarke
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Clarke
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Cunningham
authors.affiliation: Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.
authors.forename: Uday S
authors.initials: US
authors.lastname: Evani
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.affiliation: Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.|Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Fragoza
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Garrison
authors.affiliation: Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Gibbs
authors.affiliation: The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA.|Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Zeynep H
authors.initials: ZH
authors.lastname: Gümüş
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Javier
authors.initials: J
authors.lastname: Herrero
authors.affiliation: Institute for Precision Medicine and the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kitabayashi
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.|Keck Biotechnology Resource Laboratory, Yale University, New Haven, CT 06511, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Pediatric Surgical Research Laboratories, MassGeneral Hospital for Children, Massachusetts General Hospital, Boston, MA 02114, USA.|Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.|Harvard Medical School, Boston, MA 02115, USA.|Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kasper
authors.initials: K
authors.lastname: Lage
authors.affiliation: The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA.|Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY, 10065, USA.
authors.forename: Vaja
authors.initials: V
authors.lastname: Liluashvili
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Lipkin
authors.affiliation: Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.|Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.
authors.forename: Gabor
authors.initials: G
authors.lastname: Marth
authors.affiliation: Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Muzny
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.|Division of Endocrinology and Center for Basic and Translational Obesity Research, Children's Hospital, Boston, MA 02115, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Tune H
authors.initials: TH
authors.lastname: Pers
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors.forename: Graham R S
authors.initials: GRS
authors.lastname: Ritchie
authors.affiliation: Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ 07101, USA.|IST/High Performance and Research Computing, Rutgers University Newark, NJ 07101, USA.|Sackler Institute for Comparative Genomics, American Museum of Natural History, New York, NY 10024, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Sisu
authors.affiliation: Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.|Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Xiaomu
authors.initials: X
authors.lastname: Wei
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.|Child Study Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Baylor College of Medicine, Human Genome Sequencing Center, Houston, TX 77030, USA.
authors.forename: Fuli
authors.initials: F
authors.lastname: Yu
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland.|Institute for Genetics and Genomics in Geneva (iGE3), University of Geneva, 1211 Geneva, Switzerland.|Swiss Institute of Bioinformatics, 1211 Geneva, Switzerland.
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
authors.affiliation: Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, NY 14853, USA.|Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Yu
authors.affiliation: Institute for Precision Medicine and the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, NY 10065, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, CB10 1SA, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
authors.affiliation: Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.|Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.|Department of Computer Science, Yale University, New Haven, CT 06520, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Gerstein
mesh_terms: D001665:Binding Sites / Q000235:genetics; D014644:Genetic Variation; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D058977:Molecular Sequence Annotation / Q000379:methods*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011153:Population / Q000235:genetics; D022661:RNA, Untranslated / Q000235:genetics; D012641:Selection, Genetic
chemical_list: D051741:Kruppel-Like Transcription Factors; D022661:RNA, Untranslated; C497246:ZNF274 protein, human